Stickler Syndrome, Type I, Nonsyndromic Ocular
A number sign (#) is used with this entry because an atypical form of Stickler syndrome with predominantly ocular findings can be caused by mutation in the COL2A1 gene (120140).
Clinical FeaturesStickler Syndrome, Type I, Predominantly Ocular
Individuals with Stickler syndrome caused by mutations in the COL2A1 gene (Sticker syndrome type I, or STL1; 108300) almost always display a congenital vitreous abnormality consisting of a vestigial gel in the retrolental space, bounded by a highly folded membrane. In a study of 50 families presenting with the Stickler syndrome type I membranous vitreous phenotype, Richards et al. (2006) identified 3 families with a predominantly ocular form of type I Stickler syndrome in which 3 distinct mutations in the alternatively spliced exon 2 of the COL2A1 gene segregated with the respective phenotypes. The systemic features typically seen in STL1 of premature osteoarthritis, cleft palate, hearing impairment, and craniofacial abnormalities were either absent or very mild in these patients.
Korkko et al. (1993) described a family with early-onset cataracts, lattice degeneration of the retina, and retinal detachment without involvement of nonocular tissues. The findings were considered consistent with a diagnosis of Wagner syndrome (143200). Gupta et al. (2002) examined the large French-Canadian kindred originally described by Alexander and Shea (1965) as representing Wagner disease. Alexander and Shea (1965) noted epicanthus, broad sunken nasal bridge, receding chin, and genu valgum. Richards et al. (2006) suggested that the disorder in these families was more likely to be a predominantly ocular form of Stickler syndrome type I. The families studied by Korkko et al. (1993) and Gupta et al. (2002) carried mutations in the COL2A1 gene.
Wagner syndrome is often confused with Stickler syndrome. Like the predominantly ocular or ocular-only phenotype caused by certain mutations in COL2A1 (Richards et al., 2006), Wagner syndrome has no systemic features. However, the vitreoretinal phenotype is different, as neither of the recognized vitreous abnormalities in Stickler syndrome are present in Wagner syndrome and there is a lower incidence of retinal detachment. In addition, patients with Wagner syndrome have poor dark adaptation which results in night blindness; this can be demonstrated by electrodiagnosis. Finally, Wagner syndrome has been shown to be due to mutations in the CSPG2 gene (118661) which encodes versican, a proteoglycan present in the vitreous body of the eye.
Rhegmatogenous Retinal Detachment
Rhegmatogenous retinal detachment (RRD), or retinal detachment caused by a break or tear in the retina that allows fluid from the vitreous humor to enter the potential space beneath the retina, often is associated with pathologic myopia and in most cases leads to visual impairment or blindness if untreated (Go et al., 2003). Early diagnosis of RRD and recognition of patients at risk improve the prognosis. Nonsyndromic pathologic myopia (-6 diopters or less) in most cases occurs sporadically but is also encountered as an autosomal dominant or X-linked trait in families. RRD with autosomal dominant inheritance (DRRD) in association with myopia and vitreoretinal degeneration is usually described as a feature of Stickler syndrome (see 108300) or erosive vitreoretinopathy (143200).
RRD most frequently results from retinal tearing at the time of posterior vitreous detachment. Affected individuals in families with DRRD display neither of the vitreous phenotypes recognized in the Stickler syndromes and show no signs of skeletal dysplasia or deafness (Richards et al., 2005).
Molecular GeneticsStickler Syndrome, Type I, Predominantly Ocular
In 3 families with a predominantly ocular form of type I Stickler syndrome, Richards et al. (2006) found 3 distinct mutations in the alternatively spliced exon 2 of the COL2A1 gene that segregated with the phenotype. The predominantly ocular form of type I Stickler syndrome was not confined, however, to mutations in exon 2; using splicing reporter constructs they demonstrated that a mutant GC donor splice site in intron 51 can be spliced normally, thus contributing to the predominantly ocular phenotype in the family in which it occurred (120140.0049).
In 3 unrelated patients with nonsyndromic ocular Stickler syndrome, McAlinden et al. (2008) identified 2 different heterozygous mutations in exon 2 of the COL2A1 gene (120140.0051; 120140.0052). In vitro studies using a minigene construct indicated that the mutations resulted in a splicing pattern change and a decreased ratio of IIA:IIB COL2A1 mRNA. The findings suggested that the mutations were present in functional cis regulatory elements in exon 2 that are important in regulating the mechanism of alternative splicing of this exon. McAlinden et al. (2008) postulated that these mutations did not result in nonsense-mediated decay and haploinsufficiency, but rather an altered mRNA splice ratio with effects limited to the eye. Absence of an extraocular phenotype in Stickler syndrome patients with mutations in exon 2 of COL2A1 may be due to sufficient production of isoform IIB by nonsense-mediated altered splicing. Since isoform IIA is expressed in adult ocular vitreous, the ocular phenotype may be due to inadequate amounts of isoform IIA in the mature eye.
Rhegmatogenous Retinal Detachment
Go et al. (2003) investigated the clinical features and molecular causes of DRRD in 2 large families. They performed clinical examination and linkage analysis of both families using markers flanking the COL2A1 gene, which is mutant in Stickler syndrome type 1, and the loci for Wagner disease/erosive vitreoretinopathy, high myopia mapping to chromosomes 18p11.31 (MYP2; 160700) and 12q21-q23 (MYP3; 603221), and nonsyndromic congenital retinal nonattachment (221900). Fifteen individuals from family A and 12 from family B showed RRD or retinal tears with minimal (family A) or no (family B) systemic characteristics of Stickler syndrome and no ocular features of Wagner disease or erosive vitreoretinopathy. RRD cosegregated fully with a chromosomal region harboring the COL2A1 gene with maximum lod scores of 6.09 (family A) and 4.97 (family B). In family B, an arg453-to-ter mutation in exon 30 of the COL2A1 gene (R453X; 120140.0045) was identified. In family A, DNA sequence analysis revealed no mutation in the coding region or at the splice sites of the COL2A1 gene. Go et al. (2003) remarked that it was surprising that family B harbored an R453X mutation, because all predominantly ocular Stickler syndrome cases reported to that time had been associated with protein-truncating mutations in exon 2, an exon subject to alternative splicing.
Richards et al. (2005) described a family with DRRD showing no systemic clinical signs (skeletal, orofacial, or auditory) usually associated with Stickler syndrome. Linkage analysis excluded the COL11A1 gene (120280) as the disease locus but could not exclude COL2A1. Mutation screening of COL2A1 identified a gly118-to-arg mutation in the COL2A1 gene (G118R; 120140.0046). Transfection of minigenes carrying mutations associated with DRRD into cultured cells detected no missplicing of mRNA from mutant constructs. Richards et al. (2005) concluded that mutations outside the alternatively spliced exon 2 region of COL2A1 could also result in an ocular-only phenotype. The absence of evidence that missplicing modified the phenotype of these mutations suggested that the minimal or absent systemic features demonstrated by the G118R and L467F (120140.0034) mutations were the result of the biophysical changes imparted on the collagen molecule.